The development of a small animal model to study human immunodeficiency virus type-1 (HIV-1) infection would significantly facilitate studies on disease pathogenesis, as well as vaccine and anti-viral drug development and testing. However, HIV-1 replication is subjected to a number of species-specific restrictions at the level of cellular entry and/or post-entry. To date, no satisfactory small animal model for HIV-1 infection has been identified. The cotton rat has been a superb model for human infectious diseases. This animal is susceptible to an extraordinary spectrum of human pathogens, particularly viruses. Inspired by these observations, it has been cloned and characterized a battery of more than 20 cotton rat genes of immunological and inflammatory importance, and reagents for their detection has been developed. Human immunodeficiency virus (HIV-1) was shown to infect two species of cotton rats, Sigmodon hispidus and S. fulviventer and infectious virus was transmitted from animal to animal by blood. In new studies it was found that cotton rat cells (primary macrophages and a cotton rat osteosarcoma cell line) after transfection with a plasmid containing the backbone genome of HIV-1 support levels of HIV transcription analogous to those observed in human monocytes, indicating the absence of transcription blockage. Additionally, cotton rat cells became permissive to a HIV-1 pseudotyped infection when they transiently co-expressed human CD4 and CCR5 or CXCR4 chemokine receptors. The overall goal of this proposal is to generate a small animal model for HIV-1 infection by generating transgenic cotton rats expressing HIV-1 co-receptors. An HIV-1-permissive cotton rat could be widely used by the research community. At the completion of the exploratory experiments proposed for phase I of this SBIR, we will know the potential of the cotton rat as a transgenic model for HIV-1 studies, and whether is worth the time and expense to develop transgenic animals in a phase II study.